According to one aspect of this invention, it has been discovered that anesthetics of amide or ester type, such aslidocaine base, tetracaine base, propafenone or other drugs of similar structure, are highly soluble, or otherwise can be incorporated in large, effective concentrations, in conventional polymers. Under suitable conditions, the drug is found to migrate gradually and steadily to the surface of the plastic. Because of the large concentration found possible, in many cases the percentage reduction of drug present relative to the initial amount of drug, decreases only gradually with time, and provides zero order time dependence in rate over prolonged periods of use. Unique ways have been realized for employing this phenomenon. The plastic is employed as a long-term protective reservoir for the drug. In many advantageous cases, the plastic forms the exterior portion of a functional wall or component of a device as well as serving as a drug reservoir. In other cases fine particles of the plastic are employed as the reservoir. In important cases the drug is of base form and/or is more soluble in the plastic than in water. In important cases, the plastic is a hydrophobic film-forming or structural resin.
In certain instances, the plastic reservoir material itself is directly exposed to body tissue as in the case of contact with the mucosal tissue or the skin. In certain instances, one or more intervening layers are included to determine release rate to the body or to facilitate transfer of the drug to the body or to isolate the reservoir plastic from contact with body tissue. In certain cases, as in certain dermal applications, the main limit on the dosage rate is the transmissivity of the skin itself and the reservoir serves to maintain a high or selected concentration of the drug in contact with the skin surface. In other instances, the migration rate of the drug in the resin controls the release of the drug into the patient.
The phenomenon that large concentrations of the drug can be incorporated in conventional plastic resin is found to be especially applicable to FDA-approved structural and film-forming thermoplastics such as fully polymerized polyvinyl chloride (PVC). By the techniques disclosed here and in the preceding patents and patent applications referenced above, PVC in which the drug is incorporated is employed as drug-carrying granules or to coat, print or to form the structure of tubes, films, sheets, bandages, coverings, rods, foams, molded devices, sutures, other medical devices, ingestible formulations, etc.
In a wide variety of important cases the drugs in base form, when used in significant quantities, are found to demonstrate a surprising plasticizing action upon compatible plastic polymers. This facilitates the making of safe, stable and convenient products. The polymer and the drug, alone, without additional plasticizers, forms useful articles in many instances. By selection of the relative proportions of the plasticizing drug and an added therapeutically and biologically inert second plasticizer, the concentration of the drug can be selected, e.g., for selection of dosage rate, while maintaining the desired physical properties of the plastic article, such as flexibility and conformability, as in a skin patch or covering.
An anesthetizing or drug delivering effect lasting days, weeks, perhaps even months and years can be achieved by controlling the thickness of the reservoir layer, the concentration of drug present in the layer, and other parameters that govern the particular application.
The products can increase the comfort and ease of drug administration with both prescription and over-the-counter products, and in the case of anesthetic drugs, can reduce the pain of adults and children in many circumstances, reduce hospital stay, increase the use of doctor""s office and out-patient care, and increase the efficiency with which medical procedures may be accomplished.
According to one aspect of the invention, it has been discovered that effective concentrations of topical anesthetic compound at contacted tissue, suitable for maintaining topical anesthesia (concentrations that are, generally, extremely large compared to other classes of drugs) can be self-administered by a wall of a medical device by selection of particular materials and particular topical anesthetics that cooperatively meet certain selection criteria. The wall material and the topical anesthetic are selected such that (1) the necessary amount of topical anesthetic xe2x80x9cdissolvesxe2x80x9d, i.e. forms a true solution in the wall material, while (2) the topical anesthetic is more soluble in the polymer than in water and (3) the concentration of the topical anesthetic compound in the wall material is such that when the wall is in contact with a body passage, the compound diffuses to a surface of the body at a rate effective in maintaining anesthesia.
The first and third criteria assure that the needed large amount of topical anesthetic can be incorporated and uniformly administered wherever tissue contacts occurs, while the first and second criteria help to enable criteria 3 to be met by assuring that the topical anesthetic, while effective, neither causes adverse systemic reaction of the patient by too rapid release, nor is wasted too soon from the surface of the device if in contact with aqueous body fluid. These three cooperating criteria enable a sufficient concentration of the topical anesthetic to be maintained at the tissue to maintain topical anesthesia for an extended time. Thus, the patient""s long term discomfort is successfully eased.
The presently most preferred wall polymer for this aspect of the invention is polyvinyl chloride, while another preferred wall material is vinyl urethane copolymer. Presently preferred topical anesthetics for this aspect of the invention are lidocaine base, 50xe2x80x9450 mixtures of lidocaine and prilocaine and tatracaine. Dibucaine base also meets the criteria.
Applicant""s Example 1 in U.S. Pat. No. 5,279,594 dramatically demonstrates the principle. In this case polyvinyl chloride wall-forming polymer and lidocaine base anesthetic are employed. True solution of an effective quantity is achieved by exposing the wall polymer to an atmosphere containing the topical anesthetic sublimed in a vacuum chamber at elevated temperature. Note that lidocaine base is insoluble in water and thus is more soluble in the polymer than in water. This is to be distinguished from the commonly used hydrochloride or salt of this compound which is highly water soluble. The dissolved amount of 550 mg of Example 1 represents a concentration in the polymer wall of 6% (based on the weight, 8 gm, of a #16 urethral catheter); the wall was shown to maintain the anesthesia effect on the tissue. The specification expressly discloses concentrations in the polymer wall that work out to 5% (Example 3) and 10% (Example 4) that are successful in achieving the prolonged level at tissue within the body needed to maintain anesthesia on.
Unlike prior attempts, applicant""s solution to the serious discomfort problem is highly practical. The preferred combinations of topical anesthetic and wall polymer that meet the criteria are all medically acceptable materials. Further, it is found that the common sterilization technique of ethylene oxide can be used with these combinations.
In short, the tubes of the invention have a predictable capability to deliver prolonged, effective concentrations of topical anesthetic to the tissue wherever required along the tube length to maintain anesthesia.
Among the aspects shown in the related U.S. Pat. No. 5,279,594 are tubes that have topical anesthetic incorporated in the material of which the wall of the tube is composed, the anesthetic being more soluble in the wall material than in water.
Among the preferred features shown are the following. The base form of the anesthetic is employed. The entire wall thickness of a tube is formed of the anesthetic-polymer material. Materials are employed that enable ethylene oxide sterilizability. PVC and vinyl-urethane copolymer wall materials are employed.
In this first patent disclosure, the placement of an anesthetizing urethral catheter in a patient for eight hours of pain relief is also described. Also, surgery performed with topically anesthetizing endotracheal tubes in dogs is described in which it is shown to be possible to use lower concentrations of general anesthetic because of the local anesthetizing effect of the endotracheal tube.
Use of lidocaine, an acetamide, and dibucaine, an amide are shown. Specific topically anesthetizing products described are a urethral tube, an endotracheal tube, a naso-gastric tube and elastic film of anesthetizing plastic.
A number of methods for making these products are shown in this first patent, including employing a process solution to apply the anesthetic as a film to a preformed structure, from which the process solvent is subsequently evaporated; heating and pressing to cause the anesthetic to enter into solution in the plastic while forming a sheet or film; and employing gas diffusion transfer of the drug into the plastic resin.
The disclosure of the second U.S. Pat. No. 5,417,571, discloses further features including the following.
Flexible devices are described in which high concentrations of the anesthetic in base form in the plastic substances perform the function of a plasticizer for the plastic objects.
Further topically anesthetizing medical devices are shown, including nasal tubes, Foley (balloon) catheters, feeding tubes, tubes that pass through the abdominal wall and the peritoneal cavity, and drainage tubes.
Anesthetizing films, cuffs, and balloons are shown as well as loose fitting sleeves that surround medical devices inserted in the body.
The use of a barrier layer that confines the direction of diffusion of the drug from the plastic reservoir is illustrated.
Conversion of a surface layer of the anesthetic in the resin to water-soluble salt form is also described.
Products produced by extrusion and coextrusion techniques are described, as are concentrations of the anesthetic that vary across the thickness of a layer or wall, metering layers lying over the anesthetizing plastic, and use of porsigens in the plastic. Also, incorporation of the plastic in implants and use of the drug such as lidocaine for antiarrythmia medication are described.
The disclosure of the related World Pat. application, published as W095/08305 discloses further use of lidocaine and the like for antiarrythmia and antiseizure treatment. For these uses an orally ingestible form of solid particles of the drug-polymer combination is disclosed with the intention that the particles pass through the gastrointestinal tract where they release the drug and are eventually excreted.
As now explained herein, propafenone is found to enter solution or otherwise be incorporated in plastic in form enabling it to be orally administrable, or administrable by skin patch, for controlled release for antiarrythmia medication.
Principles of the invention have general applicability to drugs having at least one aromatic ring (substituted or unsubstituted benzene ring) that includes at least one free amide or amine hydrogen in its structure. In particular, drugs having at least one aromatic ring (e.g., at least one substituted or unsubstituted benzene ring), and melting point in the range of the processing temperature of thermoplastic or other heat processable resins, with the drug in base form (e.g., includes at least one free amide or amine hydrogen in its structure), can be dissolved or otherwise incorporated in effective concentrations in heat processable resin, typically at elevated temperature. In many instances, the concentrations of the drug can be very high, e.g. in excess of 10% by weight, in many cases preferably in excess of 20% by weight, and most preferably in excess of 30% or 40% by weight. For many conventional low or medium molecular weight resins having processing temperatures between about 250xc2x0 F. and 350xc2x0 F., numerous of the drugs have been found to be soluble or otherwise capable of incorporation at useful levels. For high molecular weight resins, with processing temperatures up to about 450xc2x0 F., additional drugs may be dissolved or incorporated at useful levels.
In the cooled form, the solution of resin and drug may behave as they do in conventional plastized PVC, forming, in essence, a solid gel, which, in many useful cases, has a desirable rubbery consistency. In other cases, a network of the drug is distributed through the cooled reservoir resin, in molecular, crystalline or amorphous form, that can be utilized via migration through the resin or by access pathways provided in the reservoir.
In other cases, rather than employ heat processing other techniques, including use of solvents and vapor transfer, are used to incorporate the drug in compatible resins.
In a preferred form, drugs employed according to the invention have the form:
Bzxe2x80x94Zxe2x80x94(CH2)nxe2x80x94NR1R2
where:
Bz is a substituted or unsubstituted benzene ring;
Z is an ester or amide linkage;
and each R1 and R2, individually, is Hydrogen or an alkyl group, or together form a 5 or a 6 member ring with the Nitrogen, and n is an integer.
For a desired drug, the resin system is selected to be compatible with the drug such that, at processing conditions and conditions of use, no adverse effects or reactions occur that deprive the drug of its efficacy, or the degree of mobility of the drug desired. For instance, when using thermal processing techniques, the ingredients are selected to withstand the temperatures of processing and the shear forces that are involved in the mixing, milling, or extruding that is involved and to be biocompatible when exposed to the patient.
It has been observed, specifically, according to the invention, that numerous drugs are highly soluble in polyvinyl chloride, chlorinated polyethylene and ethylene propylene, as well as in methyl methacrylate and other acrylics. It has been observed that these drugs have at least one benzene ring, are of base (e.g., free amine or amide) form. They have a lower melting point than the hydrochloric salt form of the drug, that makes them practically processable with thermoplastic resins, e.g. at temperatures in the range of about 250xc2x0 F. to 350xc2x0 F., and up to 450xc2x0 F. for high molecular weight resins.
As has been previously indicated above, it has been observed that the drugs can have a plasticizing effect on resin.
Broadly speaking, the invention is indicated to be applicable to resins or polymers in which plasticizers can be incorporated or in which phthalates, glycolates or citrate esters are soluble, or in which plasticizers or other additives with at least one aromatic ring can be incorporated.
More specifically, it has been realized that the solubility or ability to be incorporated in resins of such drugs of such molecular structure as described, in a general way, is predictable from the behavior in resins of comparable plasticizers such as phthalate, glycolate, and citrate esters which are also characterized by an aromatic ring. For the class of drugs having an aromatic ring, and especially a single aromatic ring, it can be reasonably stated that such drugs will have solubilities or the ability to be incorporated in the range of plastics in which plasticizers of similar molecular structure are soluble or can be incorporated. Phthalate esters are soluble, or can be incorporated e.g. in polymers and copolymers of polyvinylchloride, chlorinated polyethylene, cellulose nitrate, ethyl cellulose, cellulose acetate, polystyrene, polyvinyl butyryl, acrylic resins, alkyl alkylacrylates, acrylonitrile rubbers, and chlorinated rubbers such as neoprene. Drugs having a single benzene ring and structure similar to the plasticizers are likewise soluble or incorporatable in the range of resins, as a step in the preparation of a drug delivery composition.
Accordingly, further aspects of the invention include the following features. The drug has a single benzene ring; the drug of base form is soluble in resins or polymers in which phthalate, glycolate, or citrate esters are soluble; the drug has local anesthetic properties (whether or not it is generally used as a local anesthetic); the drug is an antiarrhythmic or antiseizure drug having local anesthetic properties; the antiarrhythmic drug is propafenone or lidocaine; the drug is a local or topical anesthetic medication; the drug is an adrenergic blocking drug such as atenol; the drug is a sympathomimetic drug such as pseudoephedrine, terbutaline or phenylpropanolamine; the drug is an analgesic or antipyretic such as acetaminophen, phenacetin or ibuprofen; the drug is a stimulant of the nervous system, e.g. a psychostimulant such as methylphenidate.
Structurally related drugs may be incorporated in a number of biocompatible polymers or copolymers without preventing the drug from having efficacy. Examples include resins selected from polyvinyl chloride, other polymerized vinyl halides, chlorinated polyethylene, other halogenated polyolefins, cellulosic resins such as cellulose nitrate, ethyl cellulose, cellulose acetate, polystyrene, polyvinyl butyral, alkyl alkylacrylate resins (e.g., methyl methacrylate, ethyl methacrylate), or alkyl acrylates, acrylonitrile rubbers, and halogenated rubbers (e.g., chlorinated neoprene), polyesters such as polyethylene terepthalate, polyamides such as nylon and polyformaldehyde.
Also of consequence is the realization that drugs which have an observable anesthetic characteristic (even if the main use of the drug is not for anesthesia, but for other purposes such as antiarrhythmia or other treatment of the neurophysiological system of the body) can be administered in prolonged manner by resin systems including thermoplastic resin, in which the base form of the drug has been dissolved or is otherwise incorporated.
In certain resins, certain drugs are found to be so highly soluble that the use of relatively low molecular weight resins is possible. For instance polyvinyl chloride with specific viscosity of about 225 (intrinsic viscosity of between about 96 and 99) has been demonstrated to receive in solution as much as 50% of the drugs lidocaine and the eutoclic 50% lidocaine and 50% prilocaine. Such resins are preferred when forming tube, sheet-like or fiber material in which considerable flexibility of the tube, sheet or fiber is desired.
For other applications, such as orally administratable granules of fine or coarse powders, it is desired to form an extrusion of the resin with dissolved drug, and then to grind it to form the granules. For this purpose a relatively high molecular weight, rigid resin may be preferred for ease of grinding. The high molecular weight, long molecules of such resins permit the attainment of higher processing temperatures and longer residence times in the mill or other processing equipment that is employed to dissolve or distribute the drug into the resin. This leads to increase in the amount of the drug that can be incorporated. In turn, this leads to a wider practical range of choice of the resin, permitting use of resins which have other desirable properties, such as meeting requirements of regulatory agencies and the like for prolonged use within the body, as well as to attain desirable process, storage, performance, and economic characteristics.
For those therapies in which more than one drug that is soluble in resin can be selected, another criteria for choice of the system to be employed is the fugitive or diffusive character of the drug within the particular resin. This may be estimated based upon the molecular structure of the drug, the shorter and less complicated the molecule, the more fugitive. For any particular desired therapy, demonstrations with selected drugs and resins are readily conducted to enable empirical observation. Final choice of the constituents and relationships based upon observed, reproducible results is a matter for those of ordinary skill in formulating drug and resin compositions.
As has been indicated, the discoveries described above, which arose in respect of topical anesthetics, have led to the realization that systems of the invention have generality beyond drugs that are known to have anesthetic characteristics. Thus, from the similarity of chemical structure and known characteristics of drugs, plasticizers and resins, it is realized that a wide range of drugs having sufficient unsaturated moieties, aromatic or heteroaromatic moieties, or similar structure can be delivered employing the present invention. Among these drugs are atenol, pseudoephedrine, terbutaline, phenylpropanolamine, acetaminophen, ibuprofen, phenacetin and methylphenidate.
Thus the present invention teaches and achieves new modes of drug delivery. It enables administration of drugs thought previously to have insufficient half life when administered systemically for particular therapies, and enables delivery, in prolonged fashion, of drugs that heretofore have been required to be administered at disadvantageous frequency or by disadvantageous modes.
In another aspect, the present invention teaches the applicability, in a new way, of general knowledge of the plastics industry as to compatibility of particular plasticizers, solvents, and other additives with known structural and film forming plastic systems. The molecular structure of the base form of a drug having a benzene ring, that is desired to be delivered, is compared with the molecular structure and concentrations used of proven plasticizers, solvents or additives for plastics systems. On the criteria of the similarities, a small group of candidate resins is identified. Simple mixing and heating of a substantial concentration of the drug with the resin, as between two plates under pressure, enables identification of the better combinations for compatibility of the introduced materials and enables observation of the efficacy of the system. In the case of topical anesthetic products, efficacy is readily observed based on the onset time for numbness, and the degree of numbness achieved. In other cases, migration of the drug from the novel reservoir through cadaver tissue can be observed.
To further expand upon the applicability of prior knowledge, in respect for instance of polyvinyl halide products, one should consult the literature beginning with U.S. Pat. Nos. 1,929,453, 1,983,949 and 2,188,396 to Waldo Semon, the discoverer of soluble plasticizers for polyvinyl halide products. The disclosure of those patents is hereby incorporated by reference. These references and the many references that followed, that have advanced the understanding, further indicate the plasticizer or solvent compositions with which drugs for a vinyl system can be compared. Consulting the literature readily provides similar references for other candidate resin systems in light of the present teachings.
The drug compositions according to the inventions are formulated to advantage in various ways. Resin granules are prepared such as fine or coarse powder in tablet or capsule form suitable for oral administration. The resin in orally administratable form has characteristics whereby the drug is released in the stomach and/or in the lower portion of the gastrointestinal system after which the resin is eliminated through the bowel. A protective coating on the particles may be employed to protect the composition from the acidic portions of the gastric tract.
The resin may be selected out of safety and regulatory considerations to reside as an implant or covering for prolonged periods in contact with tissue or body fluid; thus the resin may be formed as a thin, flexible wall or fiber strip or rod exposed to contact tissue; the resin is configured to perform an added function, e.g. to perform the added function of a fluid-contacting tube, feeding tube, drainage tube, or an irrigation or fluid drug administration tube or the covering of an endoscope or other examination device.
In some cases, the resin is loaded with (has dissolved or otherwise incorporated in it) a plurality of drugs, wherein the plurality includes drugs that have the same or different properties.
The resin also is advantageously configured to deliver local or topical anesthetic in the exterior region of an incision or wound, e.g. the resin is configured to form a functional bandage or compress, or a transdermal patch for intact skin.
Another aspect of the invention is a wound or incision-contacting device formed to reside beneath the closure of a surgical point, and formed at least in part of thermoplastic resin in which a topical anesthetic or other drug is dissolved or otherwise incorporated according to the invention. Such a device can reduce local pain and discomfort and promote healing.
Certain preferred embodiments of the wound or incision-contacting devices have one or more of the following features.
The device includes a drug in base form dissolved in resin and in water soluble salt form associated with the resin. The salt form is a hydrochloride salt. The device includes hydrophobic resin in which the base form is dissolved and in which the salt form is imbibed in aqueous solution in porsigens or other receptive portions or is in the form of crystal deposits that result from imbibing and subsequent drying. The device is a tube having a surface that contacts tissue to be treated. The device is a film having a surface that contacts tissue to be treated. The device is present in a compress or bandage. The device is formed at least in part of thermoplastic fibers in which the drug is present. The device is a suture formed at least in part of thermoplastic resin in which the drug is dissolved or otherwise incorporated. The fibers are at least part of a textile material. The material is a non-woven. The fibers are hydrophobic. The hydrophobic fibers are combined with hydrophilic fibers that contain an aqueous substance that promotes release and transport of the drug from the hydrophobic resin. The device comprises a cotton or other absorbent material upon which is applied, e.g. by printing or coating, in a pattern, a polymer in which the drug is incorporated. The device is combined with a fluid, ointment or adhesive that promotes transport of the drug. The fluid, ointment or adhesive contains a drug, and the drug from the resin is effective to replenish the drug in the fluid, ointment or adhesive. The drug in the fluid, ointment or adhesive and the drug dissolved or incorporated in the resin include topical anesthetics. The fluid, ointment or adhesive includes surfactant or other permeation enhancers that promote diffusion of the drug through tissue, such as the skin. The fluid, ointment or adhesive includes a thickener. The fluid, ointment or adhesive includes carboxypoly methylene (Carbopol(trademark)). The fluid, ointment or adhesive that cooperates with the drug dissolved or otherwise incorporated in the resin includes a combination of topical anesthetics and an emulsifier such as Tween(trademark) (a polyoxyethylene fatty acid ester). The combined anesthetics in the fluid, ointment or adhesive are prilocaine and lidocaine.
Another aspect of the invention is a wound or incision treating device comprising fibers or constituents of hydrophobic resin in which a drug, and especially an anesthetic base, is dissolved.
Another aspect of the invention is a wound or incision treating device comprising fibers or constituents of hydrophilic resin in which a salt form of anesthetic is imbibed or deposited as crystals.
Certain preferred embodiments of these aspects have one or more of the following features. The device comprises a combination of fibers or constituents of hydrophobic and hydrophilic resin. The fibers or constituents of both types of resin carry a drug. An aqueous solution in the hydrophilic fibers is adapted to assist in transport or migration of base-form drug in the hydrophobic resin. The aqueous solution in the hydrophilic fibers is acidic and adapted to convert the base form of the drug to a water soluble salt.
Topically anesthetizing plastic fibers, sutures and textile layers, functional bandages and compresses and methods of manufacture of such devices are also provided.
Additional important features of the invention include transdermal patches employed to apply topical anesthetic or drug to or through the skin, use of high concentrations of lidocaine as a tackifier to form a tackified methyl methacrylate-based adhesive useful as a transfer layer or as a significant drug releasing reservoir, use of plastisols for fabricating products including sheets, foams, films and coatings, formation of adherent and lubricious anesthetizing coatings and formulation of creams and other liquid suspensions and adhesives that employ solid plastic particles of e.g. PVC, in which a drug such as lidocaine is present. A drug delivery or anesthetic delivery foam ear plug, foam nasal plug, foam drug or anesthetic delivery rectal, vaginal or other suppository, a dental appliance, a sublingual or boccal insert, and anesthetizing hot water bottles, ice packs and cushions are disclosed.
Another important feature is a transparent layer, such as a film or transdermal patch, that, while cosmetically pleasing, enables topical anesthesia of the skin, to eleviate pain or prepare for minor surgical or laser procedures, hair removal, needle stick, i.v.s, etc.
FIG. 1 illustrates a view of a fiber on a much enlarged scale in which a drug is dissolved while FIG. 1a shows a small section of the fiber in a still more enlarged scale;
FIG. 2 diagrammatically illustrates a portion of the fiber magnified still more;
While FIG. 2 illustrates a spinnerette for forming the fiber.
FIGS. 3 and 4 illustrate the process of forming a non-woven using fibers according to FIG. 1.
FIG. 5 illustrates a bandage or compress formed of the non-woven of FIG. 4, while FIG. 6 shows a treatment of a non-woven.
FIG. 7 and 8 show the formation of sutures according to the invention.
FIG. 9 diagrammatically shows a compress according to the invention.
FIGS. 10-10d illustrate various stages in the manufacture of a transdermal patch, while FIGS. 10e and 10f illustrate alternative constructions;
FIG. 11 illustrates the presentation of a series of patches on a continuous sheet of release liner while FIG. 12 illustrates an elongated layer of anesthetic plastic presented in roll form.
FIGS. 13, 14 and 15 are diagrams illustrating alternative techniques for applying a plastisol coating to a substrate, for use in forming such products as are shown in FIGS. 10-12.